Tricyclic opioid modulators

Abstract

The invention is directed to compounds of Formula (I) useful as delta and mu opioid receptor modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.

1 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is hydroxy; mercapto; aminocarbonyl; C 1-4 alkanylaminocarbonyl; di(C 1-4 alkanyl)aminocarbonyl; (phenylmethyl)aminocarbonyl; (4-methoxy-phenylmethyl)aminocarbonyl; C 1-4 alkanyloxycarbonyl; aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl; 
        —C(═NOH)phenyl; amino; C 1-4 alkanylamino; di(C 1-4 alkanyl)amino; aminomethyl; hydroxymethyl; methanesulfonylamino; C 6-10 arylamino wherein C 6-10 aryl is optionally substituted with one to three substitutents independently selected from the group consisting of C 1-6 alkanyl, C 1-6 alkoxy, halogen, hydroxy; dihydroimidazolyl; formylamino; thioformylamino; or pyridinylamino; or, optionally, R 1  is —S—C(NH 2 )═N— to form a fused moiety in which the second point of attachment is an adjacent non-bridging carbon atom; 
       R 2  is a substituent selected from the group consisting of hydrogen, C 1-8 alkanyl, halo 1-3 (C 1-8 )alkanyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkanyl, cycloalkanyl(C 1-8 )alkanyl, C 1-8 alkanyloxy(C 1-8 )alkanyl, C 1-8 alkanylthio(C 1-8 )alkanyl, hydroxyC 1-8 alkanyl, C 1-8 alkanyloxycarbonyl, halo 1-3 (C 1-8 )alkanylcarbonyl, formyl, thioformyl, carbamimidoyl, phenylimino(C 1-8 )alkanyl, phenyl(C 1-8 )alkanyl, phenyl(C 1-8 )alkenyl, phenyl(C 1-8 )alkynyl, naphthyl(C 1-8 )alkanyl and heteroaryl(C 1-8 )alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl, naphthyl and heteroaryl are optionally substituted with phenyl, and one to three substituents independently selected from the group consisting of C 1-6 alkanyl, C 2-6 alkenyl, C 1-6 alkanyloxy, amino, C 1-6 alkanylamino, di(C 1-6 alkanyl)amino, C 1-16 alkanylcarbonyl, C 1-16 alkanylcarbonyloxy, C 1-16 alkanylcarbonylamino, C 1-6 alkanylthio, C 1-6 alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C 1-6 )alkanyl, thioureido, and fluoro(C 1-6 )alkanyloxy; alternatively, when phenyl and heteroaryl are optionally substituted with alkanyl or alkanyloxy substituents attached to adjacent carbon atoms, the two substituents can together form a fused cyclic alkanyl or cycloheteroalkanyl selected from the group consisting of —(CH 2 ) 3-5 —, —O(CH 2 ) 2-4 —, —(CH 2 ) 2-4 O—, and —O(CH 2 ) 1-3 O—; 
       A is (CH 2 )—; 
       Y is S; 
       and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof. 
     
   
   
       2 . The compound according to  claim 1  wherein R 1  is hydroxy, aminocarbonyl, aminothiocarbonyl; hydroxyamidino, or formylamino. 
   
   
       3 . The compound according to  claim 1  wherein R 1  is hydroxy or aminocarbonyl. 
   
   
       4 . The compound according to  claim 1  wherein R 1  is hydroxy. 
   
   
       5 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of hydrogen, C 1-8 alkanyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkanyloxy(C 1-8 )alkanyl, C 1-8 alkanylthio(C 1-8 )alkanyl, hydroxyC 1-8 alkanyl, thioformyl, phenylimino(C 1-8 )alkanyl, phenyl(C 1-8 )alkanyl, and heteroaryl(C 1-8 )alkanyl wherein heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyloxy and hydroxy; or optionally, when phenyl and heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form —O(CH 2 ) 1-3 O—. 
   
   
       6 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl, methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and heteroaryl(C 1-8 )alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group. 
   
   
       7 . The compound according to  claim 1  wherein R 2  is hydrogen, methyl, allyl, or heteroarylmethyl wherein heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl. 
   
   
       8 . The compound according to  claim 1  wherein R 2  is hydrogen. 
   
   
       9 - 13 . (canceled) 
   
   
       14 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is 6ydroxyl; mercapto; aminocarbonyl; C 1-4 alkanylaminocarbonyl; di(C 1-4 alkanyl)aminocarbonyl; di(C 1-4 alkanyl)amino-C 1-4 alkyl-aminocarbonyl; phenyl-aminocarbonyl; phenyl(C 1-4 )alkanylaminocarbonyl; C 1-4 alkanyloxycarbonyl; aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl; —C(═NOH)phenyl; amino; C 1-4 alkanylamino; di(C 1-4 alkanyl)amino; 
        aminomethyl; hydroxymethyl; C 1-4 alkanylsulfonylamino; C 6-10 arylamino wherein C 6-10 aryl is optionally substituted with one to three substitutents independently selected from the group consisting of C 1-6 alkanyl, C 1-6 alkoxy, halogen, and 6ydroxyl; dihydroimidazolyl; formylamino; thioformylamino; or pyridinylamino; or, optionally, R 1  is —S—C(NH 2 )═N— to form a fused moiety in which the second point of attachment is an adjacent non-bridging carbon atom; 
       R 2  is a substituent selected from the group consisting of hydrogen, C 1-8 alkanyl, halo 1-3 (C 1-8 )alkanyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkanyl, cycloalkanyl(C 1-8 )alkanyl, C 1-8 alkanyloxy(C 1-8 )alkanyl, C 1-8 alkanylthio(C 1-8 )alkanyl, hydroxyC 1-8 alkanyl, C 1-8 alkanyloxycarbonyl, halo 1-3 (C 1-8 )alkanylcarbonyl, formyl, thioformyl, carbamimidoyl, phenylimino(C 1-8 )alkanyl, phenyl(C 1-8 )alkanyl, phenyl(C 1-8 )alkenyl, phenyl(C 1-8 )alkynyl, naphthyl(C 1-8 )alkanyl and heteroaryl(C 1-8 )alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl, tetrazolyl, and thiazolyl; wherein phenyl, naphthyl and heteroaryl are optionally substituted with phenyl, and one to three substituents independently selected from the group consisting of C 1-6 alkanyl, C 2-6 alkenyl, C 1-6 alkanyloxy, amino, C 1-6 alkanylamino, di(C 1-6 alkanyl)amino, C 1-6 alkanylcarbonyl, C 1-6 alkanylcarbonyloxy, C 1-6 alkanylcarbonylamino, C 1-6 alkanylthio, C 1-6 alkanylsulfonyl, halogen, 7ydroxyl, cyano, fluoro(C 1-6 )alkanyl, thioureido, and fluoro(C 1-6 )alkanyloxy; alternatively, when phenyl and heteroaryl are optionally substituted with alkanyl or alkanyloxy substituents attached to adjacent carbon atoms, the two substituents can together form a fused cyclic alkanyl or cycloheteroalkanyl selected from the group consisting of —(CH 2 ) 3-5 —, —O(CH 2 ) 2-4 —, —(CH 2 ) 2-4 O—, and —O(CH 2 ) 1-3 O—; 
       A is (CH 2 )—; 
       Y is S; 
       and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof. 
     
   
   
       15 . The compound according to  claim 14  wherein R 1  is hydroxy, aminocarbonyl, hydroxyamidino, formylamino; C 1-4 alkanylaminocarbonyl; phenyl-aminocarbonyl; phenyl(C 1-4 )alkanylaminocarbonyl; C 6-10 arylamino wherein C 6-10 aryl is optionally substituted with one to two substitutents independently selected from the group consisting of C 1-4 alkanyl, C 1-4 alkoxy, halogen, and hydroxy; or pyridinylamino. 
   
   
       16 . The compound according to  claim 15  wherein R 1  is 7ydroxyl, aminocarbonyl, hydroxyamidino, formylamino; C 1-4 alkanylaminocarbonyl; phenyl-aminocarbonyl; phenyl(C 1-4 )alkanylaminocarbonyl; or pyridinylamino. 
   
   
       17 . The compound according to  claim 16  wherein R 1  is 7ydroxyl, aminocarbonyl, formylamino; phenyl-aminocarbonyl; or phenyl(C 1-4 )alkanylaminocarbonyl. 
   
   
       18 . The compound according to  claim 17  wherein R 1  is 8ydroxyl, aminocarbonyl, formylamino; phenyl-aminocarbonyl; or phenylmethylaminocarbonyl. 
   
   
       19 . The compound according to  claim 14  wherein R 2  is selected from the group consisting of hydrogen, C 1-8 alkanyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkanyl(C 1-8 )alkanyl, C 1-8 alkanyloxy(C 1-8 )alkanyl, C 1-8 alkanylthio(C 1-8 )alkanyl, hydroxyC 1-8 alkanyl, thioformyl, phenylimino(C 1-8 )alkanyl, phenyl(C 1-8 )alkanyl, and heteroaryl(C 1-8 )alkanyl wherein heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl, tetrazolyl; wherein phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyloxy and 8ydroxyl; or optionally, when phenyl and heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form —O(CH 2 ) 1-3 O—. 
   
   
       20 . The compound according to  claim 19  wherein R 2  is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, 3-methyl-but-2-enyl, propynyl, hydroxyethyl, C 3-5 cycloalkanylmethyl, methylthioethyl, methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and heteroaryl(C 1-2 )alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl, tetrazolyl; wherein the phenyl in any phenyl-containing substituent and the pyridinyl substituent are optionally substituted with one hydroxyl group. 
   
   
       21 . The compound according to  claim 20  wherein R 2  is hydrogen, methyl, allyl, 3-methyl-but-2-enyl, cyclopropylmethyl, phenylmethyl, or heteroarylmethyl wherein heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl. 
   
   
       22 . The compound according to  claim 21  wherein R 2  is hydrogen, methyl, 3-methyl-but-2-enyl, cyclopropylmethyl, phenylmethyl, 9yridine-2-ylmethyl, 9yridine-3-ylmethyl, 9yridine-4-ylmethyl, 2-hydroxy-pyridin-4-ylmethyl, imidazol-2-ylmethyl, thien-2-ylmethyl, or furan-3-ylmethyl. 
   
   
       23 .- 30 . (canceled) 
   
   
       31 . A compound of Formula (Ib) 
     
       
         
         
             
             
         
       
       selected from the group consisting of 
       a compound of Formula (Ib) wherein R 1  is aminocarbonyl, A is —(CH 2 ) 2 —, and R 2  is H; and 
       a compound of Formula (Ib) wherein R 1  is aminocarbonyl, A is —(CH 2 ) 2 —, and R 2  is trifluoromethylcarbonyl. 
     
   
   
       32 . A composition comprising the dextrorotatory enantiomer of a compound of formula (I) wherein said composition is substantially free from the levorotatory isomer of said compound. 
   
   
       33 . A composition comprising the levororotatory enantiomer of a compound of formula (I) wherein said composition is substantially free from the dextrorotatory isomer of said compound. 
   
   
       34 . A pharmaceutical composition comprising a compound, salt or solvate according to any of  claim 1  admixed with a pharmaceutically acceptable carrier, excipient or diluent. 
   
   
       35 . A veterinary composition comprising a compound, salt or solvate according to  claim 1  admixed with a veterinarily acceptable carrier, excipient or diluent. 
   
   
       36 .- 47 . (canceled) 
   
   
       48 . A kit comprising in one or more containers an amount of the composition of  claim 1  effective to treat or prevent mild to severe pain. 
   
   
       49 . A pharmaceutical composition comprising a compound, salt or solvate according to  claim 14  admixed with a pharmaceutically acceptable carrier, excipient or diluent. 
   
   
       50 . A veterinary composition comprising a compound, salt or solvate according to  claim 14  admixed with a veterinarily acceptable carrier, excipient or diluent. 
   
   
       51 .- 57 . (canceled) 
   
   
       58 . A kit comprising in one or more containers an amount of the composition of  claim 14  effective to treat or prevent mild to severe pain. 
   
   
       59 .- 101 . (canceled)